DIABESITY

INTRODUCTION

In recent decades, the global healthcare landscape has witnessed a significant rise in the prevalence of two interconnected health issues, diabetes and obesity. As these conditions frequently coexist, they have become to be known as “diabesity”. This chapter aims to explore the diabesity epidemic, its underlying causes, and impact on public health. By examining the historical context, risk factors, consequences, and possible solutions, we can gain a comprehensive understanding of this complex and urgent health crisis.

HISTORICAL CONTEXT

The diabesity epidemic did not emerge overnight. Historical records reveal that the prevalence of diabetes and obesity has been on a steady rise for more than a century. In the early 20th century, both conditions were relatively rare with type 2 diabetes mellitus (T2DM) primarily affecting older individuals and obesity being less prevalent due to physical labor and limited access to calorie-dense foods. However, factors such as urbanization, sedentary lifestyle, rising pollution, and changes in dietary patterns gradually contributed to the emergence of diabesity.

RISK FACTORS

A range of factors contribute to the development of diabesity such as genetic predisposition, poor dietary choices, sedentary lifestyle, pollution, and socioeconomic influences. Genetic factors play a role in determining an individual’s susceptibility to obesity and diabetes, but the rapid increase in diabesity prevalence cannot be attributed solely to genetics. Environmental factors, such as the availability of highly processed foods and sedentary behaviors, have contributed significantly to the rise of diabesity. Rising rates of pollution are closely linked to insulin resistance and the emergence of other noncommunicable diseases as well. Socioeconomic disparities also play a crucial role, as individuals from low-income backgrounds often face limited access to nutritious foods and opportunities for physical activity.

CONSEQUENCES

Diabesity carries a multitude of health consequences, both on an individual and societal level. The combination of diabetes and obesity increases the risk of developing chronic conditions, such as cardiovascular disease, hypertension, depression, osteoarthritis, urinary incontinence, obstructive sleep apnea, and certain types of cancer. Moreover, diabesity poses a considerable burden on healthcare systems worldwide, leading to increased healthcare costs and reduced productivity. It also affects the quality of life for those living with these conditions, impacting physical, mental, and emotional well-being.

ADDRESSING THE EPIDEMIC

Tackling the diabesity epidemic requires a comprehensive and multidimensional approach. Efforts should focus on prevention through public health interventions, education, and policy changes. Key strategies include promoting healthy eating habits, increasing physical activity opportunities, implementing sugar and calorie reduction measures, and improving food labeling. Collaboration between governments, healthcare professionals, community organizations, and the food industry is vital to successfully address diabesity.

CONCLUSION

The diabesity epidemic represents a significant global health challenge. With the prevalence of diabetes and obesity continuing to rise, urgent action is required to reverse this trend. By addressing the root causes and implementing prevention strategies, it is possible to alleviate the burden on individuals, healthcare systems, and society at large. Increased awareness, education, and support are crucial to empower individuals to make healthier choices and adopt sustainable lifestyle modifications. Through concerted efforts, we can strive toward a healthier future where diabesity is no longer an epidemic.

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS

INTRODUCTION

Incretin hormones are the hormones released from the small intestine which lead to oral glucose-dependent stimulation of insulin secretion from beta-cells of the pancreas. With the discovery of the incretin pathway and understanding the pathophysiological abnormalities of the incretin system, drugs targeting the incretin system were developed. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were thus discovered and were utilized for the treatment of incretin dysfunction in T2DM. Recently, liraglutide and semaglutide have been approved for weight reduction in obesity independent of glycemic status.

MECHANISM OF ACTION

Glucagon-like peptide-1 receptor agonists activate the GLP-1 receptors in the pancreas, which leads to enhanced glucose-dependent insulin release with a low risk for hypoglycemia. They also act to preserve pancreatic islet cell mass, reduce glucagon secretion by alpha cells, reduce hepatic steatosis, and are potent antiobesity medications (by activating anorexigenic arm of energy homeostasis in the hypothalamus). GLP-1 RAs slow gastric emptying, activate pro-opiomelanocortin (POMC) neurons in the hypothalamus, and indirectly inhibit expression of orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons via gamma-aminobutyric acid (GABA)-dependent signaling. They also suppress mesolimbic dopaminergic reward system via GABA-signaling. GLP-1 RAs also act on extrahypothalamic nuclei in the brain and lead to activation of the sympathetic nervous system (SNS), and cause thermogenesis and energy expenditure. In addition to being potent glucose-lowering agents, GLP-1 RAs have shown significant reductions in body weight, blood pressure, non-high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and inflammation.

Glucagon-like peptide-1 receptor agonists have demonstrated significant cardiovascular and renal benefits in terms of reduction of atherosclerotic cardiovascular diseases (ASCVDs) and worsening diabetic kidney diseases (DKDs). In cardiovascular outcome trials, GLP-1 RAs have proven to be superior to placebo with significant reductions in 3-point major adverse cardiac events (MACE) consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, and cardiovascular mortality.

AVAILABILITY, USE, AND ADVERSE EFFECTS

Amongst the injectable GLP-1 RAs, only liraglutide, dulaglutide, and exenatide are currently available and approved for use in India. GLP-1 RAs are administered subcutaneously. They can be stored at room temperature (15–30°C). GLP-1 RAs are contraindicated in individuals with a personal or family history of medullary thyroid cancer (MTC), or multiple endocrine neoplasia type 2 (MEN2), pregnancy, history of pancreatitis, or allergy to excipients of the respective GLP-1 RA. Gastrointestinal adverse events are the most common and include nausea and vomiting, diarrhea or constipation, dyspepsia, gastroesophageal reflux disease, gastroenteritis, abdominal pain, and abdominal distension and flatulence, which usually wanes over time. Other adverse effects include headache, fatigue, dizziness, eructation, suicidal ideation, and nasopharyngitis.

EFFICACY

Glucagon-like peptide-1 receptor agonists lead to robust improvements in glycemic parameters, and semaglutide, in particular, leads to significant and meaningful reductions in body weight. GLP-1 RAs have also been shown to improve hepatic steatosis (Table 1).

CONCLUSION

Glucagon-like peptide-1 receptor agonists are a powerful class of antidiabetic medications, which have proven glycemic control, weight loss, cardioprotective benefits, and antisteatotic properties. They are an invaluable inclusion in the armamentarium for treating T2DM and obesity.

SUGGESTED READINGS

1.   Magliano DJ, Boyko EJ (Eds). IDF Diabetes Atlas, 10th edition. Brussels: International Diabetes Federation; 2021.

2.   World Obesity Federation. (2020). Obesity Fact Sheet. [online] Available from https://www.worldobesityday.org/assets/downloads/Obesity_Factsheet_Final_%28website%29.pdf [Last accessed December, 2023].

3.   Popkin BM, Gordon-Larsen P. The nutrition transition: worldwide obesity dynamics and their determinants. Int J Obes Relat Metab Disord. 2004;28(Suppl 3):S2-9.

4.   Piché ME, Tchernof A, Després JP. Obesity Phenotypes, Diabetes, and Cardiovascular Diseases. Circ Res. 2020;126(11):1477-500.

5.   Caruso I, Di Gioia L, Di Molfetta S, Cignarelli A, Palmer SC, Natale P, et al. Glucometabolic outcomes of GLP-1 receptor agonist-based therapies in patients with type 2 diabetes: a systematic review and network meta-analysis. EClinicalMedicine. 2023;64:102181.